Inborn error of metabolism, involving

An inborn error of metabolism involves a missing or deficient enzyme which causes a block on a metabolic pathway. 

Three inborn errors of metabolism involving enzymes of the urea cycle have been demonstrated. These diseases are observed in children less than a year old. They all cause hyperammonemia and have a characteristic neurological and gastrointestinal symptomatology nausea, vomiting, agitation, convulsions, stupor, coma, and general mental retardation (see Fig. 9-14). 

As classically viewed, the inborn errors of metabolism involve a mutation in a structural gene, causing an amino acid substitution or deletion affecting the active site of the protein. Defects in enzyme regulation can lead to a loss of modulation of metabolic pathways, with an overproduction of the terminal product without gross accumulation of... 

Wellner, V.P., Sekura, R., Meister, A. andLarsson, A. (1974), Glutathione synthetase deficiency, an inborn error of metabolism involving the y-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Proc. Natl. Acad. Sci. U.S.A., 71, 2505. 

Understanding of the degradative pathways for GAGs, as in the case of glycoproteins (Chapter 47) and glycosphingohpids (Chapter 24), has been gready aided by elucidation of the specific enzyme deficiencies that occur in certain inborn errors of metabolism. When GAGs are involved, these inborn errors are called mucopolysaccharidoses (Table 48—7). 

If this is so, then the next question to be answered is What metabolic peculiarities are crucial with respect to susceptibility to alcoholism It is obvious that the answer to this question must be based upon some knowledge of metabolic peculiarities in general. What metabolic peculiarities exist from which one might choose the crucial ones Because of lack of attention to biochemical individuality, little indeed was known about metabolic peculiarities. When we began the study of alcoholism, the list of known peculiarities was pretty much limited to the relatively rare so-called "inborn errors of metabolism," alcaptonuria, phenyl ketonuria, cystinuria, and the like. The chance that any of these were involved was very minute. 

Since Williams and co-workers proposed the genetotrophic concept in 1950,20, 21 many genetotrophic diseases have been discovered. Stark examples include the so-called nutrient "dependencies" and other nutrition-responsive inborn errors of metabolism.22, 23 More subtle cases include all the complex diseases now being found to involve both nutrition and genetic predispositions. 

Inherited absence or mutations in enzymes involved in critical metabolic pathways—eg, the urea cycle or glycogen metabolism—are referred to as inborn errors of metabolism. If not detected soon after birth, these conditions can lead to serious metabolic derangements in infants and even death. 

Because of these ever-widening interests, the measurement of plasma tHcy is undertaken in many clinical chemistry and routine laboratories. Various methods are employed, including high-performance liquid chromatography (HPLC) assays, conventional amino acid analysis, capillary electrophoresis, gas chromatography with or without mass spectrometry, liquid chromatography with tandem mass spectrometry, and in many routine clinical chemistry laboratories immunoassays. In this chapter, those methods that are often available in laboratories involved in the investigation of inborn errors of metabolism are described, namely HPLC and tandem mass spectrometry. 

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

The answer is a. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 97-158. Wilson, pp 23-39.) Autosomal recessive conditions tend to have a horizontal pattern in the pedigree. Men and women are affected with equal frequency and severity. It is the pattern of inheritance most often seen in cases of deficient enzyme activity (inborn errors of metabolism). Autosomal recessive conditions tend to be more severe than dominant conditions and are less variable than dominant phenotypes. Both alleles are defective but do not necessarily contain the exact same mutation. All individuals carry 6 to 12 mutant recessive alleles. Fortunately, most matings involve persons who have mutations at different loci. Since related persons are more likely to inherit the same mutant gene, consanguinity increases the possibility of homozygous affected offspring. 

The significance of the complex sequence of events involved in the formation, transfer, and clearance of plasma lipoprotein CE is demonstrated dramatically by several inborn errors of metabolism. One such error is familial LCAT deficiency [67]. In this disease, as well as in diseases associated with acquired LCAT deficiency, LCAT activity in the plasma is abnormally low, and many hpoprotein and tissue abnormalities are observed. The content of UC and PC is abnormally high, and the molar ratio of UC to PC in the hpoproteins is also high, sometimes reaching a value of nearly 2 1. In association with these abnormahties, most lipoproteins show an abnormally low content of CE. In addition, there are abnormahties in the distribution and/or concentration of apolipoproteins AI, All, B, C, and E disc-shaped HDL and unusually small spherical HDL are seen and multilamehar vesicles containing UC and PC are usually present in the LDL fraction obtained by preparative ultracentrifugation. These abnormahties all seem to depend on the LCAT deficiency they are altered toward normal when patient plasma is incubated with LCAT in vitro. 

Information concerning the relative importance of metabolic pathways may be obtained from studies on inborn errors of metabolism. Two such disorders affecting bile acid biosynthesis have been described, cerebrotendinous xanthomatosis (CTX) and Zellweger s disease (cerebro-hepato-renal syndrome). The primary defect in cerebrotendinous xanthomatosis seems to be the absence of one enzyme involved in bile acid biosynthesis. The basic defect in Zellweger s disease has not yet been defined with certainty. 

The feature of all inherited disorders is a genetic defect, often the result of a single base substitution or deletion in the DNA. which results in the reduced synthesis of a particular protein or in the synthesis of a protein with an altered amino acid coniposiiion. A classical inborn error of metaholisni involves a missing or defective en/yme which causes a block on a metabolic pathway and the production of toxic metabolites. More than four thousand disorders involving single genes have been identified. 

Mutations leading to deficiencies in enzymes are usually referred to as inborn errors of metabolism, because they involve defects in the DNA of the affected individual. Errors in enzymes that catalyze reactions of amino acids frequendy have disastrous consequences, many of them leading to severe forms of mental retardation. Phenylketonuria (PKU) is a well-known example. In this condition, phenylalanine, phenylpyruvate, phenyllactate, and phenylacetate all accumulate in the blood and urine. Available evidence suggests that phenylpyruvate, which is a phenylketone, causes mental retardation by interfering with the conversion of pyruvate to acetyl-CoA (an important intermediate in many biochemical reactions) in the brain. It is also likely that the accumulation of these products in the brain cells results in an osmotic imbalance in which water flows into the brain cells. These cells expand in size until they crush each other in the developing brain. In either case, the brain is not able to develop normally. 

Some patients have an inborn error of metabolism that involves a defective enzyme, or enzymes of the urea cycle. This results in reduced efficiency to excrete their waste nitrogen. The patients are prescribed sodium phenylbutyrate (buphenyl) ( 30 g per day). What is the action of sodimn phenylbutyrate ... 

Williams and Sweeley (1964) have given methods for the chromatographic separation of many urinary aromatic acids and have discussed diagnostic applications to (1) secreting tumors, e.g., malignant carcinoid, pheochromocytoma, and neuroblastoma, and (2) inborn errors of metabolism, e.g., tyrosinosis, phenylketonuria, Hartnup disease (involves aminoaciduria), and other inherited diseases. These authors referred to the use of infrared spectroscopy for verification of the identity of fractions of volatile organic anesthetics in blood. Chlorpromazine, pentobarbitone, and amphetamine, are examples of pharmacological substances that have been separated (Scott, 1966). 

The work of several generations of biochemists working with physicians insured that by 1973, 93 inborn errors of metabolism had been listed. Most of these detailed discoveries of the biochemical pathways and the enzymes involved in metabolic disease were made between 1957 and 1973 [213]. 

For further details of ammo acids involved in specific inborn errors of metabolism, there is a recent review by Wellner and Meister (1981). A review article such as this or the new edition of Metabolic Basis of Inherited Diseases (Stanbury et al., 1983) should be checked first when attempting to assess the significance of a particular amino acid pattern seen m a patient. A review article of more general significance, such as that by Applegarth et al., (1983), may also be helpful. An excellent book that contains much valuable information on analytical problems and clinically relevant material is also available (Shih, 1973), and should be consulted for further background information... 

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